Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches
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Zaripova et al. Pediatric Rheumatology (2021) 19:135
https://doi.org/10.1186/s12969-021-00629-8
REVIEW Open Access
Juvenile idiopathic arthritis: from
aetiopathogenesis to therapeutic
approaches
Lina N. Zaripova1 , Angela Midgley2, Stephen E. Christmas3, Michael W. Beresford2,4, Eileen M. Baildam4 and
Rachel A. Oldershaw1*
Abstract
Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatological disorder and is classified by
subtype according to International League of Associations for Rheumatology criteria. Depending on the number of
joints affected, presence of extra-articular manifestations, systemic symptoms, serology and genetic factors, JIA is
divided into oligoarticular, polyarticular, systemic, psoriatic, enthesitis-related and undifferentiated arthritis. This
review provides an overview of advances in understanding of JIA pathogenesis focusing on aetiology,
histopathology, immunological changes associated with disease activity, and best treatment options. Greater
understanding of JIA as a collective of complex inflammatory diseases is discussed within the context of
therapeutic interventions, including traditional non-biologic and up-to-date biologic disease-modifying anti-
rheumatic drugs. Whilst the advent of advanced therapeutics has improved clinical outcomes, a considerable
number of patients remain unresponsive to treatment, emphasising the need for further understanding of disease
progression and remission to support stratification of patients to treatment pathways.
Keywords: Juvenile idiopathic arthritis, Pathogenesis of juvenile idiopathic arthritis, Aetiology of juvenile idiopathic
arthritis, Disease-modifying anti-rheumatic drug treatment
Introduction and classification The International League of Associations for Rheuma-
Juvenile idiopathic arthritis (JIA) unifies all forms of tology (ILAR) stratifies subtype of autoimmune inflam-
chronic childhood arthritis, affecting not only joints, but matory disorders, determined by the number of joints
extra-articular structures, including eyes, skin, and in- affected, the presence of systemic symptoms and detec-
ternal organs, leading to disability and even associated tion of rheumatoid factor (RF). JIA is divided into the
fatality. It is defined as the presence of arthritis of un- sub-forms: oligoarticular (persistent or extended), poly-
known aetiology that begins before the age of 16 and articular (RF-negative or RF-positive), systemic (sJIA),
persists for at least 6 weeks [1]. psoriatic arthritis and enthesitis-related arthritis, with
each differing in genetic susceptibility and severity of
arthritis [1]. Any arthritis that does not fit into these cat-
* Correspondence: lrao1@liverpool.ac.uk
1
Department of Musculoskeletal and Ageing Science, Institute of Life Course egories or corresponds to > 1 subtype is considered as
and Medical Sciences, University of Liverpool, William Henry Duncan undifferentiated [2]. The main characteristics of arthritis,
Building, 6 West Derby Street, Liverpool L7 8TX, UK
internal organ involvement, genetic predisposition, la-
Full list of author information is available at the end of the article
boratory markers of each subtype and adult equivalent
are shown in Table 1.
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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.Zaripova et al. Pediatric Rheumatology (2021) 19:135 Page 2 of 14
Table 1 The main clinical and laboratorial characteristics of JIA subtypes based on International League of Associations for
Rheumatology (ILAR) classification criteria. ANA – antinuclear antibodies, Anti-CCP – Anti-Cyclic Citrullinated Peptide, CRP - C-reactive
protein, ERA - enthesitis-related arthritis, HLA - human leukocyte antigen system, RF – rheumatoid factor, sJIA – systemic JIA
Subtype Oligoarticular Polyarticular JIA RF- Polyarticular JIA RF+ ERA Psoriatic JIA Systemic sJIA
JIA
Characteristic • ≤4 joints • ≥5 joints affected• • ≥5 joints affected• • Lower limb joints • Asymmetric • Usually arthralgias;•
of arthritis affected• Symmetric or Symmetric• Mainly affected more arthritis• Small 30–50% chronic
Mainly large asymmetric• Small small joints common• Axial and large arthritis - slowly
joints• and large joints• (metacarpophalangeal involvement: joints developed• Mostly
Asymmetric, Sometimes a joints and wrists)• sacroiliac joint, hip wrists, knees, ankles
often only a cervical spine and/ Erosive• Aggressive or shoulder joints or
single joint or symmetric polyarthritis asymptomatic
(knee) temporomandibular temporomandibular
joint arthritis
Systemic 30% uveitis 10% uveitis • Rheumatoid nodules• • Acute anterior • Psoriasis• • Spiking fever•
manifestation 10% uveitis uveitis• EnthesitisGut Dactylitis• Generalized
inflammation Onycholysis• lymphadenopathy•
Nail pitting• Migratory salmon-pink
Uveitis (10– rash• Serositis (pericar-
15%) ditis most common,
then pleuritic and
peritonitis)• Hepatos-
plenomegaly• MAS
Sex Female Female Female Male Equal Equal
predominance
HLA genetic Associated Associated with• A2• Associated with• Associated with• B27• Associated Associated with• DRB1:
pre- with• A2• DRB1*08• DPB1:03• DRB1*04• DRB1*01• DRB1*01• DQA1*01• with• DRB1*01• 04• DQA1*01• DQB1*04•
disposition DRB1*11• DQA1*04• DRB1*08• DQA1*03 DQB1*05 DRB1*11• DRB1*01
DRB1*08• DRB1*15*01• DRB1*12• HLA-
DPB1*0201• DPB1*02*01 C*06 -
DRB1*15*01• biomarker for
DQA1*04• skin
DQB1*04• involvement•
DRB1*13 for B27 – for
persistent• sacroileitis
DRB1*01 for (mostly in
extended variant older age)
Biomarkers 60% ANA+ 40% ANA+ • RF+• Anti-CCP+• ANA+ 45–85% HLA-B27+ 50% ANA+ Elevating level of• CRP•
in 40% Ferritin• Platelets
Adult – Potential RF-positive Rheumatoid Spondyloarthropathies Psoriatic Adult Onset Still’s
equivalent Seronegative Arthritis Arthritis Disease
Rheumatoid Arthritis
Oligoarticular JIA is characterised by inflammation of disease belonging to the group of spondyloarthropathies
up to four joints that archetypically proceeds as asym- [1]. Psoriatic arthritis often proceeds as oligoarthritis or
metrical arthritis predominantly affecting the joints of RF-negative polyarthritis and involves more commonly
the lower extremities, such as knee and ankle, with high the small joints accompanied by dactylitis, psoriatic rash
frequency of positivity to anti-nuclear antibody (ANA) and/ or nail pitting [1, 3]. Psoriatic JIA itself is described
and high risk of chronic uveitis [3]. Polyarticular JIA as a heterogeneous disease where children < 6 years are
(pJIA) affects five or more large/ small joints and is hall- more likely to be female, ANA-positive and predisposed
marked by injury to the metacarpophalangeal joints and to chronic uveitis, with arthritis of wrists and small
wrists [4]. Both RF-positive and negative variants have joints of the hands and feet. In older children disease is
characteristic clinical features. RF-negative pJIA, inflam- associated with HLA-B27 positivity, enthesitis and axial
mation can be asymmetrical, but for RF-positive pJIA disease with male predisposition [5].
symmetric involvement of the large and small joints of Standing apart from other subtypes, sJIA manifests not
hands and feet is the most prevalent. Enthesitis-related only with widespread joint arthritis, but also with a sig-
arthritis (ERA) resembles oligoarthritis, affecting the nificant range of systemic inflammation symptoms
joints of the lower limb in association with enthesitis. (Table 1) [6]. Approximately 10% of sJIA patients
Due to the association with lower limb and sacroiliac present systemic symptoms with associated macrophage
joints, enthesitis, uveitis and the association with HLA- activation syndrome (MAS), a potentially life-
B27, Ravelli et al. (2007) have suggested ERA to be a threatening condition with histopathological featuresZaripova et al. Pediatric Rheumatology (2021) 19:135 Page 3 of 14
that include the accumulation of terminally- Histopathology of JIA
differentiated macrophages with high hemophagocytic The main hallmark of JIA is joint inflammation with tissue
activity [7, 8]. Currently the limitations of the ILAR clas- destruction [11]. Within the synovial joint, the synovial
sification scheme are pertinent and include the absence membrane thickens in response to uncontrolled prolifera-
of link to pathogenesis, molecular pathways and re- tion of synoviocytes and immunocompetent cells, includ-
sponse to the therapy [9]. In addition, there is a substan- ing T-cells, B-cells, natural killers, neutrophils,
tial unclassified cohort of patients with JIA onset before macrophages, dendritic cells and plasma cells that infil-
6 years of age and female predominance having specific trate the sub-lining layer of the synovium (Fig. 1) [11].
features that include symmetric arthritis, iridocyclitis, Hyperplasia and hypertrophy of the synovium causes
ANA and HLA-DR8-positivity. In 2019 the Pediatric intraarticular hypoxia, increasing the production of pro-
Rheumatology International Trials Organization angiogenic mediators and initiating pathological angio-
(PRINTO) Consensus revised the ILAR classification cri- genesis [12]. Increased concentrations of vascular endo-
teria and proposed to identify this complex of features thelial growth factor (VEGF), a potent endothelial cell
as early-onset ANA-positive JIA [10]. Other JIA disor- (EC) mitogen, its soluble receptors-1 and -2 (sVEGF-R1,
ders identified according to these preliminary criteria in- sVEGF-R2), and osteopontin (OPN), a chemotactic fac-
clude sJIA, RF-positive JIA and enthesitis/spondylitis- tor that activates mononuclear cells, have been corre-
related JIA (Table 2). Arthritis of more than 6 weeks lated to synovial angiogenesis assessed by Doppler
duration that does not fit the criteria is grouped as ultrasonography of JIA patients [12]. Angiopoietin-1
‘Other JIA’, and that fitting more than one criterion, ‘un- (Ang-1), another pro-angiogenic EC mitogen with a role
classified JIA’ [10]. PRINTO Consensus highlights JIA as in stabilisation of newly formed vessels was also shown
not a single disease but a group of different disorders, of to be upregulated in JIA. New blood vessel formation
which diagnosis does not require joint count or the pres- within the synovium increases blood supply and the mi-
ence of arthritis. The onset of the disease has been chan- gration of pro-inflammatory cells into the joint, forming
ged to before 18 years of age [10]. a pathological synovium, known as ‘pannus’ (Fig. 1).
Table 2 The preliminary criteria of the main JIA disorders proposed by the Pediatric Rheumatology International Trials Organization
(PRINTO) Consensus. The PRINTO classification proposed systemic JIA (sJIA), rheumatoid factor–positive JIA (RF+ JIA), enthesitis/
spondylitis-related JIA and early-onset antinuclear antibody–positive (early-onset ANA+) JIA. ANA – antinuclear antibodies, AOSD -
adult-onset Still’s disease, Anti-CCP – Anti-Cyclic Citrullinated Peptide, HLA - human leukocyte antigen system, RA – rheumatoid
arthritis, RF – rheumatoid factor, y.o. – years old
JIA Early-onset ANA+ JIA RF+ JIA Enthesitis/ sJIA
disorders spondylitis-
related JIA
Clinical • Arthritis for ≥6 weeks, • Arthritis for ≥6 • Peripheral • Fever with exclusion of infectious, neoplastic, autoimmune,
criteria and weeks arthritis and or monogenic autoinflammatory diseases, for at least 3 days
• Early-onset (≤ 6 y.o.) enthesitis, or and reoccurring over 2 weeks
• Arthritis or + 2 major criteria or 1 major criterion and 2 minor criteria
enthesitis, + Major criteria:
≥ 3 months of • evanescent erythematous rash
sacroiliitis, or • arthritis
• Arthritis or Minor criteria:
enthesitis + 2 of - generalized lymphadenopathy and/or hepatomegaly and/or
the following: splenomegaly
- sacroiliac joint - serositis
tenderness - arthralgia lasting more than 2 weeks
- inflammatory
back pain
- acute anterior
uveitis
- history of a SpA
in relative
Laboratory • 2 “+” ANA tests with a • 2 positive tests for - presence of HLA- - leukocytosis (≥ 15,000/mm3) with neutrophilia
criteria titer ≥1/160 at least 3 RF at least 3 months B27 antigen
months apart apart or
• 1 positive test for
anti-CCP
Adult – RF-positive RA Spondyloarthritis AOSD
equivalentZaripova et al. Pediatric Rheumatology (2021) 19:135 Page 4 of 14 Fig. 1 Schematic diagram showing the differences between the normal and JIA joint. The pathological process within the JIA synovial joint is characterised by uncontrolled proliferation of synoviocytes resulting in increased number of layers and thickening of the synovial membrane; rapid pathological angiogenesis; formation of pathological synovium, “pannus”, with uncontrolled growth and invasive properties; accumulation of granulocytes, macrophages, plasma cells, lymphocytes and the production of inflammatory mediators, provoking synovitis. Created with BioRender.com Granulocytes, macrophages, plasma cells and lympho- biomechanical strength and the ability to smoothly ar- cytes accumulate in the subintima of the joint and pro- ticulate the joint [2, 13]. Pro-inflammatory cytokine- duce pro-inflammatory mediators including tumour mediated activation of receptor activator of nuclear necrosis factor-α (TNFα) and interleukin (IL)1β, upregu- factor-kappaB (RANK)-expressing osteoclasts results in lating pannus-synoviocyte production of catabolic prote- bone erosion [14]. Damage to cartilage and bone in the ases including matrix metalloproteinases (MMPs, advanced stages of JIA causes ankyloses and the loss of particularly MMP1 and MMP3), aggrecanases and ca- movement in the affected joints. Considering that JIA is thepsins, that breakdown the extracellular matrix of the a disease of the developing body, patients with JIA are articular cartilage tissue causing loss of function, likely to suffer from disruption of skeletal growth [15].
Zaripova et al. Pediatric Rheumatology (2021) 19:135 Page 5 of 14 Aetiology ERAP2) predispose to ERA, while genes encoding IL1, The heterogeneity of JIA disease subtypes adds complex- IL6, IL10 and MIF increase the risk of sJIA, which itself ity to the investigation of cause and mechanism of is considered as a genetically distinct subtype of JIA [16]. pathogenesis, and the initiating factors of JIA remain un- resolved [16]. Pathogenesis of JIA Environmental factors, including infectious agents, JIA subtypes represent a heterogeneous group of dis- vaccinations, antibiotics, vitamin D deficiency, stress and eases with multifactorial and different pathogenesis trauma have been proposed as risk factors. Infectious vi- (Table 3). It is not completely understood how the com- ruses (Epstein-Barr virus, Parvovirus B, Rubivirus, Hepa- bination of the environmental triggers and genetic sus- titis B virus) and bacteria (Salmonella spp., Shigella spp., ceptibility disrupt the balance between regulatory and Campylobacter spp., S. pyogenes, B. henselae, M. pneu- effector cells in the pathogenesis of JIA. moniae, Chlamydophila pneumonia) have been reported as causal factors provoking JIA [17]. Gastrointestinal in- Immunological changes fection leading to loss of gut microbiome diversity and Initiation of the JIA pathophysiological cascade includes disrupted tryptophan metabolism increases the risk of abnormal activation of T-cells, B-cells, natural killer ERA [18]. Carlens et al. (2009) reported that maternal (NK) cells, dendritic cells (DC), macrophages and neu- smoking during pregnancy increased the probability of trophils and the production of pro-inflammatory media- an immune imbalance during foetal development leading tors that cause joint destruction and systemic to the onset and progression of paediatric arthritis [19]. complications. In contrast, some beneficial factors such as breast feed- Oligoarticular and pJIA are characterised by autoreac- ing and household siblings might decrease the risk of de- tive antigen-specific T-cells and high titres of autoanti- veloping JIA [20]. bodies, and typically shows strong associations with Several studies have documented genetic associations MHC class II alleles. Breakdown of immunologic self- to JIA [21–25]. Genetic linkage depends on subtype and tolerance involves MHC class II alleles suggesting a piv- may be divided into two groups: HLA genes and non- otal role for CD4+ T helper (Th) cells [21]. Inflamma- HLA-related genes. Meta-analysis of genetic predispos- tion is considered to be a consequence of disrupted ition to JIA subtypes has shown association with HLA balance between pro-inflammatory Th1/Th17 and anti- class II molecules (A2, DRB1, DPB1) mostly for non- inflammatory regulatory T-cells (Treg). The decrease in systemic subtypes (Table 1), while for sJIA the lack of Treg cells is inversely correlated with an increase in the association with HLA genes has been found [21]. Oli- Th17 cell population and occurs from the differentiation goarticular JIA is associated with A2, DRB1*11, of naïve T-cells by influence of IL1β [26]. Differentiation DRB1*08, DPB1*02, DRB1*13, DRB1*15*01 and of naive T-cells into Th-cells results in the production of DRB1*01, while for RF- polyarticular the most com- pro-inflammatory cytokine IL17, which may induce pro- monly associated genes are DPB1:03 and DRB1:08, and duction of IL6, MMP1 and 3, IL8 (a chemoattractant for for RF+ JIA, DRB1*04 and DRB1*01 [23]. Of interest, neutrophils) by synoviocytes, resulting in subsequent HLA-A, HLA-B and HLA-DR were observed in females joint destruction [16, 26]. Prelog et al. (2008) revealed with oligoarthritis but not males, which may point to premature immunosenescence of T-cells in oligoarticu- disease heterogeneity [2]. The main gene associated with lar, pJIA and sJIA patients, as indicated by the loss of ERA is HLA-B27, with other genes predisposing the de- compensatory proliferation of naive T-cells, increased velopment of ERA being DRB1*01, DQA1*01, and telomeric erosion, and loss of capability of the thymus to DQB1*05 [18]. HLA-B27 is also found in late-onset produce T-cell receptor excision circles [27]. psoriatic JIA [5].Genetic pre-disposition of non-HLA- Association with HLA class II and the presence of related genes plays a pivotal role in the onset of inflam- ANA suggests that an adaptive immune response is pre- matory response leading to tissue damage. Genes encod- dominant in the pathogenesis of oligoarticular JIA. How- ing cytokines TNF, IL2, IL10, IL6, macrophage ever, activated neutrophils with altered phenotype and migration inhibitory factor (MIF), protein tyrosine phos- dysfunction, and impaired synovial monocytes and mac- phatase (PTPN22), signal transducer and activator of rophages with reduced capacity to phagocytose have re- transcription-4 (STAT4), solute carrier family-11 (pro- cently been identified in synovial fluid of patients with ton-coupled divalent metal ion transporters), member-1 oligoarticular JIA [28, 29]. Together with high levels of (SLC11A1), natural resistance-associated macrophage monocyte-derived cytokines this emphasises the import- protein-1 (NRAMP1) and WNT1-inducible signalling ance of the innate immune system in oligoarticular JIA pathway protein-3 (WISP3) have all been associated with pathogenesis [28, 29]. JIA [2, 21, 23]. Polymorphism in genes encoding endo- The pathogenesis of ERA is driven by HLA-B27- plasmic reticulum resident aminopeptidases (ERAP1 and mediated presentation of arthritogenic peptide following
Zaripova et al. Pediatric Rheumatology (2021) 19:135 Page 6 of 14
Table 3 Differences in the pathogenesis between oligoarticular, polyarticular rheumatoid factor (RF)-negative and positive, systemic
(sJIA), psoriatic arthritis and enthesitis-related arthritis (ERA). As an autoinflammatory disease sJIA is different in pathogenesis, clinical
manifestations, and therapeutic strategy compared to non-systemic subtypes of JIA. ANA - Antinuclear antibodies, anti-MCV -
antibodies against mutated citrullinated vimentin, anti-CCP - anti-cyclic citrullinated peptide, IL - interleukin, MIF - macrophage
migration inhibitory factor, PsJIA – psoriatic JIA, RF – rheumatoid factor, sJIA – systemic JIA, TNF - tumour necrosis factor
Oligoarticular JIA Polyarticular JIA ERA Psoriatic JIA sJIA
Type of Autoimmune Autoimmune Autoimmune Early-onset PsJIA – Autoinflammatory
disease autoimmune,
while
late-onset PsJIA –
autoinflammatory
Immune Adaptive immune Adaptive immune Adaptive immune system Adaptive immune Innate immune system
system mainly system system system in early-
involved in onset PsJIA
pathogenesis Innate immune
response in late-
onset PsJIA
Gene MHC class II MHC class II HLA-B27 HLA-B/C, HLAB, TNF, IL6, IL10, MIF, IL1
association IL12B, IL23R, TNP1,
TRAF3IP3, REL
HLA-B27 in late-
onset PsJIA
Antibodies ANA ANA ANA may be positive in some cases ANA in the early- –
RF, anti-CCP, anti- onset PsJIA
MCV – for RF+ JIA
Predominant CD4+, CD8+ T-cells, CD4+, CD8+ T- γδT-cells, Th17 cells Th1 and Th17 cells Monocytes, macrophages,
effector cells neutrophils cells subsets, neutrophils
macrophages
Key moment Imbalance between Imbalance HLA-B27 involved in presentation of Autoinflammatory Abnormal activation of
in inflammatoryTh1/ between pro- unidentified arthritogenic peptide caused activation at the phagocytes leads to
pathogenesis Th17 and Treg cells inflammatory Th1/ T-cells activation and induction of endo- synovial-entheseal hypersecretion of pro-
Th17 and Treg plasmic reticulum stress complex inflammatory cytokines
cells Autoimmune
processes in extra-
articular tissues
Main pro- TNFα, IL17, IFNγ TNFα, IL17, IL33, TNFα, IL17, IL23 IL17, IL23 IL1, IL6, IL18, IL37, LRG
inflammatory IFNγ and ADA2
cytokines
Main Inhibition of T-cell Inhibition of T-cell Block of TNFα Inhibition of T-cell Block of IL1 and IL6
treatment proliferation, rarely proliferation, block proliferation, block signalling pathway
targets anti-TNFα therapy of TNFα of TNFα
is needed
T-cell activation and IL23 and IL17 secretion. Bowel Standing apart from non-systemic subtypes that are
wall inflammation usually accompanied with ERA is known as autoimmune disorders, sJIA has been suggested
driven by γδT cells, innate lymphoid cells type-3 or to be an autoinflammatory pathology with different patho-
Th17 cells and IL17 and IL23 production [18]. Enthesitis genesis [16]. In sJIA, uncontrolled activation of the innate
is triggered by repeated biomechanical stress stimulation immune system results in activation of monocytes/macro-
resulting in microtrauma and release of fibronectin, hya- phages, neutrophils and immature (CD34 + CD33+) mye-
luronan, and other molecular components from dam- lomonocytic precursors, and increased production of pro-
aged connective tissue, which may directly activate inflammatory cytokines IL1β, IL6, IL18 and phagocyte-
synovial macrophages, stromal cells and IL23 production specific S100 proteins [16, 30, 31]. MAS is a complicated
to establish a positive feedback loop. Interestingly, the sJIA, where some triggers (bacterial or viral infections,
pathogenesis of late-onset psoriatic JIA resembles ERA drugs) cause uncontrolled expansion of cytotoxic CD8+
with entheses inflammation and inflammation in the T-cells that produce pro-inflammatory cytokines and
bowel wall [5]. Early-onset psoriatic JIA is characterised propagate the induction and activation of hemophagocytic
by adaptive immune mechanisms involvement with de- macrophages that infiltrate bone marrow and multiple or-
velopment of dactylitis [5]. gans in particular the liver and spleen [8].Zaripova et al. Pediatric Rheumatology (2021) 19:135 Page 7 of 14 Inflammatory cytokines cytokine, IL37 was found to be significantly elevated in There is a significant and predominant pro- plasma and IL-37 mRNA expression has been shown to inflammatory cytokine signature in the plasma and syn- correlate with disease activity and production of pro- ovial fluid of patients with JIA. JIA patients demonstrate inflammatory cytokines IL6, TNFα and IL17 [39]. high levels of TNFα, MIF, macrophage inflammatory The collective data available to date, suggests that protein (CCL3), macrophage-derived chemokine cytokine patterns may be appropriate for accurate dis- (CCL22), monokine induced by IFNγ (CXCL9), mono- ease classification in early JIA with the potential as tar- cyte chemoattractant protein-1 (CCL2) and IFNγ- gets for improving diagnosis and treatment strategies for induced protein-10 (CXCL10) in blood and synovial patients with paediatric autoimmune disease [33]. fluid [32]. Comparison of patients with different sub- types showed significantly higher concentrations of Autoantibody production plasma CCL11, CXCL10 and CCL2 in oligoarticular JIA Serological biomarkers in JIA patient tissues may be compared to sJIA, while patients with sJIA demonstrated stratified into those that are stable and persistent higher level of IL1, IL6 and IL18 in serum [32, 33]. Ele- throughout disease course (including antibodies such as vated levels of IL33 are observed in patients with RF+ RF) and those that change over time and disease activity polyarticular JIA in comparison with oligo- and RF+ (including cytokines such as IL18). ANA, RF, anti-cyclic polyarticular JIA, and are correlated with disease activity, citrullinated peptide (anti-CCP) and antibodies against indicative of being a potential biomarker candidate for mutated citrullinated vimentin (anti-MCV) are reported pJIA disease activity [34]. The concentrations of MIF, in non-systemic JIA pathogenesis [40, 41]. RF is an anti- IL10 and IL17 in serum or synovial fluid is predictive for body specific to the Fc portion of IgG; it was first de- oligoarticular JIA (with less than 60% accuracy). MIF, scribed as a key serological marker in patients with adult IL17 and IL23 are also increased in ERA [18]. IL18 is rheumatoid arthritis (RA) and then identified in a small predictive for sJIA (with 93% accuracy) [32], and plays a sub-group of pJIA patients (only 5% of total JIA patients) pivotal role in the pathogenesis of MAS, with an in- [4]. RF-positivity is associated with severe prognosis of creased concentration reported to be predictive of MAS JIA and rapid formation of bone erosions [40]. ANA is complication in sJIA patients [35]. Martini et al. (2012) considered to be common for oligoarticular, polyarticu- showed the correlation between elevated levels of pro- lar, psoriatic subtypes of JIA, and associated with in- inflammatory cytokine IL6 in sJIA with the severity of crease the risk of uveitis in JIA patients [42]. Anti-CCP joint inflammation and microcytic anaemia due to IL6 and anti-MCV typically characterise RF-positive pJIA influence on erythropoiesis by increasing the synthesis and may predict more severe and erosive disease pro- of iron-lowering hormone hepcidin [6]. gression needing earlier and more intensive therapy [40, Leucine-rich α2-glycoprotein (LRG), induced by pro- 43]. Anti-CCP activates complement and macrophages inflammatory cytokines IL1, IL6 and TNFα, promotes by crosslinking TLR4 and Fc gamma receptors and indu- differentiation and proliferation of Th17 cells and is cing TNFα production by binding to the macrophage present in the sJIA and MAS correlated with serum CRP Fcγ receptor IIa in vitro. Patients double positive for and ferritin levels [36]. Adenosine deaminase-2 (ADA2), Anti-CCP and RF have higher levels of TNFα, IL1β, IL6 released by monocytes and macrophages following and IL17 [41]. stimulation with IL18 and IFNγ is considered to be a novel biomarker of MAS, being strongly correlated with Establishing diagnosis and prediction of ferritin, IL18 and CXCL9 [37]. complications Anti-inflammatory cytokines are also involved in the Clinical symptoms, family history, laboratory markers progression of JIA [16]. The pleotropic effects of both and instrumental examinations (ultrasound and mag- transforming growth factor-beta (TGFβ) and IL10 im- netic resonance imaging) are used to determine JIA sub- pact on the control of innate and adaptive immunity. type. Physical examination findings are paramount and Thus, TGFβ1 directly targets T-cells leading to the include signs of arthritis (pain, tenderness, stiffness and established immune tolerance to self- and environmental swelling of synovial joints) and extra-articular findings antigens. IL10 mediates anti-inflammatory actions by in- (such as rash, lymphadenopathy, dactylitis, nail changes). duction of heme oxygenase-1, a stress-inducible protein Laboratory tests for HLA-B27, RF or anti-CCP antibody with anti-inflammatory properties, and through the in- identifies the subtype of JIA and the risk of bone ero- duction of mammalian target of rapamycin (mTOR) in- sions and joint damage. Myeloid-related protein (MRP)8, hibitor [38]. Thus, the clinically inactive disease, in the MRP14 and IL18 may be used as biomarkers for active absence of medication in some patients, may represent sJIA, whereas HLA-B27 is predictive of ERA [41]. ANA compensation of the autoimmune activity by anti- and RF are useful for the diagnosis of oligo and pJIA inflammatory cytokines [16]. Another anti-inflammatory subtypes [41]. ANA is associated with increased risk of
Zaripova et al. Pediatric Rheumatology (2021) 19:135 Page 8 of 14
chronic non-granulomatous uveitis, which is the most dose corticosteroids provides good short-term effect, espe-
common extra-articular manifestation of JIA and is typ- cially in sJIA patients, but has no influence on the long-
ically asymptomatic but has an elevated risk of causing term disease outcome. Moreover, its prolonged adminis-
visual impairment. Aljaberi et al. (2020) reported higher tration is associated with severe side effects including
levels of pro-inflammatory calcium-binding S100 pro- osteoporosis, growth suppression, immunosuppression
teins in sJIA patients compared to other autoinflamma- and metabolic effects (Table 4) (48).
tory syndromes. However, other studies have revealed The American College of Rheumatology (ACR) recom-
that high baseline S100A12 concentration is associated mends early use of DMARDs, specifically MTX, lefluno-
with higher disease activity and response to methotrex- mide and/or sulfasalazine (Table 4) [48]. MTX is
ate (MTX) and anti-TNF therapy in patients with JIA in- considered to be the first choice DMARD for oligo- and
cluding pJIA, ERA, oligoarticular and psoriatic arthritis pJIA when NSAIDs and intraarticular steroids are insuf-
[44]. Thus, S100A8/9 and S100A12 proteins are subclin- ficient [49–51]. MTX is also considered to be effective
ical inflammation markers that may help with diagnosis in children with PsJIA, though the axial manifestations
and monitoring disease activity [45]. limits prescription of MTX and so TNF inhibitors are
Recent history of gastrointestinal or urinary infection, typically required in these cases [5]. Leflunomide may be
gut inflammation confirmed by elevated fecal calprotec- used as an alternative DMARD for pJIA in cases of
tin levels, sacroiliitis with inflammatory spinal changes MTX intolerance [52, 53]. Sulfasalazine is recommended
and enthesitis detected by MRI support diagnosis of for patients with moderate activity of ERA with active
ERA [18]. Subclinical gut inflammation has also been peripheral arthritis, but is inefficient in case of sacroiliitis
identified in older-onset of psoriatic JIA [5]. [18, 54]. The Clinical Commissioning Policy Statement:
The diagnosis of sJIA in accordance with ILAR criteria Biologic Therapies for the treatment of Juvenile Idio-
requires arthritis and fever within the last 2 weeks, and pathic Arthritis (2015) reports that in 30–50% of pa-
one of the following criteria: rash, generalised lymph- tients where disease continues to progress, advanced
adenopathy, enlargement of liver or spleen, or serositis biologics are the next therapeutic step.
[46]. Common laboratory abnormalities suggestive of The first biological drugs registered for the treatment
systemic inflammation include elevated erythrocyte sedi- of JIA were anti-TNFα agents, etanercept and adalimu-
mentation rate (ESR), C-reactive protein (CRP), white mab. Etanercept was approved for the treatment of pJIA
blood cell count, platelet count, ferritin, transaminases, in 1999, based on a randomised, placebo-controlled
aldolase and d-dimers help to define the activity of the double-blind study evaluation of safety and efficacy [55].
disease [47]. Laboratorial analysis of patients with active Now TNFα inhibitors are recognized to be the most ef-
sJIA may reveal granulocytosis, thrombocytosis, anaemia, fective drugs for the treatment of JIA with influence on
upregulation of acute phase reactants (elevated erythro- pain, stiffness, growth and quality of life and were first
cyte sedimentation rate (ESR) and C-reactive protein successful in the treatment of pJIA, then ERA, psoriatic
(CRP), which are typical findings but not so essential for and oligoarthritis subtypes [48, 56, 57]. Combination of
diagnosis in comparison with the life-threatening com- TNFα blocking agents with MTX increases the oppor-
plication of MAS that include pancytopaenia, increased tunity of achieving JIA remission in patients with these
levels of ferritin, liver enzymes (aspartate and alanine subtypes and is an effective option in uveitis-associated
transaminases), triglycerides, d-Dimers and hypofibrino- JIA [58]. In a randomized double-blind trial anti-TNF
genemia [7]. Clinical findings of MAS include high non- agents namely etanercept or adalimumab have proven
remitting fever, generalised lymphadenopathy, hepatos- effective for ERA [18].
plenomegaly, central nervous system dysfunction and For pJIA that is nonresponsive to at least one DMARD,
hemorrhagic manifestations. including TNFα inhibitors, abatacept (CTLA4-Ig) may be
recommended [54, 59] following demonstration of long-
Treatment term efficacy, safety and improvement of quality of life in
Therapeutic intervention begins at diagnosis with non- 58 JIA patients for 7 years [59]. Another option should
steroidal anti-inflammatory drugs (NSAIDs) followed by TNFα inhibition reach sub-optimal clinical outcomes for
disease-modifying anti-rheumatic drugs (DMARDs, most pJIA is the IL6 receptor inhibitor, tocilizumab. Toci-
often methotrexate) and/or corticosteroid intra-articular lizumab might also be a treatment option for JIA-related
injection. In blocking prostaglandin production via inhib- uveitis refractory to MTX and TNF inhibitors [60].
ition of cyclooxygenase-1 and cyclooxygenase-2, NSAIDs For many years anti-TNFα therapy demonstrated im-
obtain both analgesic and anti-inflammatory effects. Local proved treatment outcomes for all forms of JIA but were
corticosteroid joint injections are effective in synovitis and less effective for sJIA, where the therapeutic approach
may be a first-line treatment for oligoarthritis alone or in has been IL1β/IL6 signalling blockade [56, 61–63]. Toci-
addition to DMARDs. Systemic administration of high lizumab (anti-IL6R) was the first approved medicationZaripova et al. Pediatric Rheumatology (2021) 19:135 Page 9 of 14
Table 4 The mechanism of action and side effects of commonly used medications for JIA treatment. DMARDs - disease-modifying
anti-rheumatic drugs, GC – glucocorticoids, ERA - enthesitis-related arthritis, IL - interleukin, NK - natural killer, MAS – macrophage
activation syndrome, MTX – Methotrexate, sJIA – systemic JIA, TNF - tumor necrosis factor
Drug Mechanism of Action Therapeutic Options Adverse Event Reference
Non-Biologic DMARDs
MTX • MTX is a structural analogue of folic • Polyarticular JIA• Oligoarticular JIA• • Nausea• Oral ulceration• Infections [49–51, 53,
acid that inhibits dihydrofolate JIA-related uveitis refractory to top- (herpes zoster)• Severe 54]
reductase and DNA synthesis• Acts ical treatment• sJIA with predomin- complications in less than 1% of
in different pathway: cytokine ant joint inflammation and without cases include:- Cirrhosis-
production, arachidonic acid active systemic symptoms• Psoriatic Pneumonitis- Leucopenia-
metabolism and cell apoptosis JIA Thrombocytopenia- Anaemia
Leflunomide • Inhibition of T-cell proliferation by • Polyarticular JIA patients who • Diarrhoea• Rashes• Cytopenia• [52]
blocking pyrimidine synthesis cannot tolerate MTX• Used rarely in Abnormal liver-function test•
pediatric patients because of its Teratogenicity
teratogenicity and long half-life
Sulfasalazine • Immune-suppressive effect not fully • ERA with moderate activity, but not • Gastrointestinal toxicity• [18, 54]
established in other types of JIA Sulphonamide allergy•
Neuropsychiatric complications
(headache, anxiety)• Pancytopenia•
Pneumonitis• Myelosuppression•
Hypogammaglobulinaemia
Biologic DMARDs
TNF inhibitors
Adalimumab • Subcutaneous recombinant human • JIA patients with resistance or • Risk of reactivation of latent [58]
IgG1κ monoclonal antibody• intolerance to MTX• Polyarticular infections such as tuberculosis, and
Neutralises TNFα by binding with JIA• JIA with uveitis• ERA refractory new infections caused by viruses,
soluble and membrane-bound TNF to sulfasalazine• Psoriatic JIA fungi, or bacteria• Rare reports of:-
Lymphoma- Demyelinating central
nervous system disorders- Cardiac
failure
Infliximab • Intravenous chimeric monoclonal • Polyarticular JIA where there has • Opportunistic infections: herpes, [56, 57]
antibody against TNFα• Binding with been the use of MTX for at least 3 tuberculosis, pseudomonas
soluble and transmembrane TNFα, months with poor response• pneumonia, reactivation of hepatitis
that mediates complement and Uveitis• Psoriatic JIA B, fungal infection
antibody-dependent cytotoxicity of
expressed TNFα cells (macrophages
and monocytes)
Etanercept • Fusion protein consisting of the • Polyarticular JIA with resistance or • Central nervous system events [54–56]
extracellular domain of the human intolerance to MTX• ERA• Psoriatic (headache, neuritis)• Varicella
p75 TNFα receptor• Linked to the Fc JIA infections• Rare:- Malignancy
region of human IgG1, binds and
inhibits soluble TNFα
IL1 inhibitors
Anakinra • Recombinant IL1 receptor • Refractory sJIA with persistent - Vomiting, nausea, diarrhea- [61, 63]
antagonist binds to IL1 receptors systemic symptoms• MAS Headache- Abdominal pain- Upper
(IL1r1)• Inhibits the binding of IL1α respiratory and urinary tract
and IL1β infections- Neutropenia
Canakinumab • Human Monoclonal antibody• • sJIA patients with continued • Thrombocytopenia• Neutropenia• [64]
Selectively blocks IL1β disease activity after treatment with Upper respiratory tract infection•
GC monotherapy and MTX or Cough• Abdominal pain•
leflunomide, anakinra or Gastroenteritis, vomiting, diarrhea•
tocilizumab Pyrexia• Very rare:- pneumococcal
sepsis
Rilonacept • Fusion protein between the Fc • Active sJIA • Infections• Developed elevations in [67]
portion of IgG and the IL1 receptor• liver transaminases• High cholesterol
Blocks the interaction of IL1 with or triglycerides• Abdominal pain•
cell surface receptors preventing IL1 Gastroenteritis, nausea, diarrhea
signalling
T-cell inhibitors
Abatacept • Inhibitor of naïve T-cell activation• • Severe sJIA• Polyarticular JIA • Bacterial and opportunistic [54, 59]
Soluble fusion protein of CTLA-4 patients with inadequate response infections• Rare:- acute
with the Fc portion of IgG that to MTX and TNF-blockers lymphoblastic leukemiaZaripova et al. Pediatric Rheumatology (2021) 19:135 Page 10 of 14
Table 4 The mechanism of action and side effects of commonly used medications for JIA treatment. DMARDs - disease-modifying
anti-rheumatic drugs, GC – glucocorticoids, ERA - enthesitis-related arthritis, IL - interleukin, NK - natural killer, MAS – macrophage
activation syndrome, MTX – Methotrexate, sJIA – systemic JIA, TNF - tumor necrosis factor (Continued)
Drug Mechanism of Action Therapeutic Options Adverse Event Reference
binds to CD80/CD86 and blockades
signal following MHC-peptide: TCR
engagement necessary for T cell
activation
IL6 inhibitors
Tocilizumab • Humanised monoclonal antibody • sJIA• Polyarticular JIA with • Headache• Upper respiratory tract [30, 31]
against the IL6 ubiquitous receptor resistance and continued disease infections (more than 10%)•
(IL-6R)• Block IL6 signaling pathway activity after treatment with MTX Varicella, herpes zoster•
by binding to cell-surface and sol- and TNF-blockers Neutropenia• Elevation of
uble IL-6R aminotransferases
Anti-B-cells therapy
Rituximab • Chimeric monoclonal antibody • JIA refractory to anti-TNF agents • Infusion reactions (headache, throat [54, 70]
against B-cells with mouse variable and standard immunosuppressive irritation, rash, itchiness, pyrexia) in
and human constant regions• Binds therapy one third of patients• Bacterial
CD20 on the surface of B-cells form- infections• Hepatitis B reactivation•
ing a cap that allow NK cells to des- Rare:- cardiac arrest- cytokine
troy B cells• Leads to B-cell death release syndrome- multifocal
and removal from circulation leukoencephalopathy- pulmonary
toxicity
Janus Kinase (JAK) inhibitors
Tofacitinib • Inhibit JAK1 and JAK3• Interrupt the • Refractory polyarticular JIA• sJIA • Diarrhea• Headache• High blood [74]
JAK-STAT signalling pathway, which refractory to other therapy pressure• Upper respiratory tract
is responsible for the transmission of infections• Varicella zoster virus
extracellular multiple proinflamma- reactivation• Cytomegalovirus
tory cytokines, including IL-6, into infection• Pulmonary embolism•
the nucleus, leading to changes in Rare:- Lymphoma or other
DNA transcriptome malignancies
Other medications
Glucocorticoids • Binding to glucocorticoid receptors √ Systemic steroids for:• sJIA with • Infections• Myopathy• [48]
(GC) inhibits calcium and sodium cycle serious organ involvement (including Neuropsychiatric symptoms•
across plasma membranes, reducing pericarditis, myocarditis)• Patients Osteoporosis• Obesity• Insulin
activation and proliferation of with features indicative of MAS• High resistance• Cushing syndrome•
immune cells• Post-transciptional disease activity in oligo- and Gastric ulcer• Cataract• Glaucoma
destabilisation of messenger RNA polyarticular JIA• Intraarticular
resulting in reduced production of steroids for oligo- and polyarticular
proinflammatory cytokines including JIA
IL1 and IL6
Cyclosporine A • A fungal cyclic polypeptide• Binds to • sJIA with indication of MAS • Nausea• Headache• Renal [48]
the cellular protein cytophilin, complications• Neuronal
resulting in inhibition of the enzyme complications (paresthesia),•
calcineurin• Specifically and Hepatotoxiety
reversibly inhibits CD4+
immunocompetent lymphocytes in
the G0-G1 phase of the cell cycle•
Then inhibits IL2 production and re-
lease by T-helpers
for the treatment of active sJIA, demonstrating safety corticosteroid-dependent patients with sJIA in a rando-
and efficacy in two multicentre studies of patients with mised, double-blind, placebo-controlled trial and showed
sJIA and pJIA [31]. Other studies have shown the effi- that anakinra is less effective on arthritis than on sys-
cacy of IL1 blockade in sJIA [61]. Complete remission temic symptoms [63]. Currently, anakinra (IL1Ra), rilo-
was obtained in seven out of nine patients with refrac- nacept (IL1 inhibitor) and canakinumab (anti-IL1β) have
tory sJIA treated with recombinant IL1 receptor antag- been successfully studied in clinical research with com-
onist anakinra (the other two patients demonstrating a parable long-term efficacy where half of treated patients
partial treatment response) [62]. However, Quartier achieved remission [61, 64–67]. IL18 may be another
et al. (2011) reported a short-term effect of this drug in target for treatment of sJIA resistant to IL1 and IL6Zaripova et al. Pediatric Rheumatology (2021) 19:135 Page 11 of 14 inhibition, as far as higher levels of IL18 have been asso- achieved remission even with less aggressive treatment ciated with high ferritin levels reported in MAS [68, 69]. [79]. MAS as a form of hemophagocytic lymphohistiocytosis is usually treated with high-dose methylprednisolone and cyclosporine A (a calcineurin inhibitor). In relation Disease course, quality of life and functional to biological therapies, treatment of MAS has been suc- outcome cessful using IL1 receptor antagonist anakinra (IL-1Ra) Substantial progress in JIA treatment has been made and rituximab (anti-CD20) [70], which has also demon- over the last three decades. Clinical outcomes have dra- strated efficacy in other immunological disorders, in- matically improved, with disease control and remission cluding SLE [61]. Other promising therapeutics, possible in most patients. Nevertheless, a significant pro- tadekinig alfa (anti-IL18) and emapalumab (anti-IFNγ) portion of patients have ongoing disease activity. In fact, are currently undergoing clinical trials with data report- about half of patients continue to require active treat- ing safety and potential efficacy for the treatment of sJIA ment into adult life, whereas complete remission is and MAS [71, 72].Another new class of biological achieved in only 20–25% of patients [80, 81]. DMARDs are the Janus-associated tyrosine kinases Administration of biological agents has decreased (JAK) inhibitors. The mechanism of their action consists the mortality rate of JIA from 1 to 4% in 1970s to of blocking JAK-STAT pathways to interrupt the trans- 0.3–1% in 2016 [82]. Improved clinical outcomes in duction of extracellular pro-inflammatory signals into physical disability are reflected in the Steinbrocker the cell nucleus. The efficacy of first generation of JAK functional classification scale. Between 1976 and 1994, inhibitors (namely tofacitinib and baricitinib) were first 15% of JIA patients were within Class III (limited to explored in adults with RA, and then in other immune- few or no activities of the patient’s usual occupation) mediated inflammatory diseases such as ankylosing and Class IV (bedridden with little or no self-care), spondylitis, SLE, inflammatory bowel disease and psoria- compared to 5% in 2002 [83]. However, joint damage, sis [73]. Tofacitinib was effectively used in case of refrac- occurring before treatment led to surgical intervention tory sJIA [74]. Miserocchi et al. (2020) showed in 14% of patients, emphasising the importance of effectiveness of tofacitinib and baricitinib in 4 cases of early aggressive treatment to achieve complete remis- JIA uveitis, defined by a reduction of intraocular inflam- sion [84]. The prominent factor influencing treatment mation according to Standardized Uveitis Nomenclature outcome is presence of systemic manifestation. Multi- criteria, and no side effects were registered [75]. The re- organ failure in patients with MAS is fatal in approxi- sults of a randomised phase 3, multinational, double- mately 8% of cases [8]. blind, controlled clinical trial (NCT02592434) has Being the most frequent extraarticular manifestation proven the safety and effectiveness of tofacitinib in pJIA, JIA-associated uveitis became the main cause of vision resulting in reduced flares and disease activity [76]. On- loss in childhood, and furthermore about half of these going trials are investigating baricitinib (NCT04088396, patients suffer from active uveitis in adulthood [85]. NCT03773978, NCT04088409) and tofacitinib (NCT03 Additionally, a high risk of osteoporosis and conse- 000439) in patients with other JIA disorders [77].Recent quently fractures in early adulthood remain higher in therapeutic advances including combination of DMAR JIA patients even in remission [15]. Ds, corticosteroids and the biological agents reduce Long-term outcomes of JIA patients are dependent on synovitis, tissue damage progression and systemic com- subtype and disease activity, which may remain elevated plications, making low disease activity an achievable goal for many years including into adulthood. In early adult- in JIA. Early treatment with biologics may be important hood about half of patients with JIA have active disease in controlling disease activity and avoiding steroids and approximately 30% suffer from some form of dis- altogether or at least reducing the duration of use. How- ability [80]. Selvaag et al. (2016) reported a 59% remis- ever, long-term prescription of biologic agents due to sion rate in patients with JIA after 30 years but noted immune suppression increases the risk of opportunistic the low quality of life in adults with JIA [81]. infections and potentially even malignancy (the main ad- Comorbidities and complications highlight the status verse events are shown in the Table 4) [56]. Early ag- of JIA as the most important paediatric rheumatological gressive treatment of JIA was shown to be beneficial pathology that may continue with remissions and flares with 40% of patients achieving clinical inactive disease throughout life, leading to impairment of connective tis- within 6 months [78], though some serious adverse sue and the reduction of life quality. There is a need for events was registered during treatment (such as pneu- more discovery science research to help the understand- monia, septic joint, elevation of transaminases, periton- ing of the complexity of the inflammatory process and sillar abscess, recurrent herpes simplex). It may be to enable the development of treatments that may come suggested that some of these patients would have with the promise of an actual cure.
Zaripova et al. Pediatric Rheumatology (2021) 19:135 Page 12 of 14
Conclusions review. LNZ, AM, SEC, MWB, EMB, RAO were involved in the creation and
JIA is a chronic rheumatic disease of childhood, charac- revision of manuscript drafts. LNZ, AM, SEC, MWB, EMB, RAO authors read
and approved the final manuscript.
terised by progressive joint destruction and serious sys-
temic manifestations. Complex interactions between Funding
immune cell populations, including lymphocytes, mono- This review article was undertaken as part of research funded by a Bolashak
Scholarship Award, Kazakhstan Government, to Dr Lina Zaripova to
cytes, macrophages and neutrophils, trigger the patho- undertake a PhD at the University of Liverpool, Liverpool, UK, and also by the
physiological cascade in JIA. Our review of clinical Wellcome Trust Institutional Strategic Support Fund awarded to the
research has demonstrated that the heterogeneity of University of Liverpool (grant number 097826/z/11/z).
non-systemic and sJIA pathogenesis stratifies JIA pa-
Availability of data and materials
tients by subtype, with requirement for differing thera- Not applicable.
peutic approaches. A broad range of DMARDs such as
T-cell inhibitors, anti-TNFα agents, IL1 and IL6 Declarations
blockers, JAK inhibitors have significantly improved the Ethics approval and consent to participate
clinical management of JIA. However, further research is Not applicable.
needed to deepen our understanding of the complexity
Consent for publication
of the inflammatory process in JIA and to enable the de- Not applicable.
velopment of effective treatments that improve upon
clinical outcomes and disease remission. Competing interests
The authors declare that they have no competing interests.
Abbreviations
JIA: Juvenile idiopathic arthritis; ILAR: International League of Associations for Author details
1
Rheumatology; RF: Rheumatoid factor; sJIA: Systemic juvenile idiopathic Department of Musculoskeletal and Ageing Science, Institute of Life Course
arthritis; ERA: Enthesitis-related arthritis; pJIA: Polyarticular JIA; and Medical Sciences, University of Liverpool, William Henry Duncan
PRINTO: Pediatric Rheumatology International Trials Organization; Early-onset Building, 6 West Derby Street, Liverpool L7 8TX, UK. 2Department of Women
ANA+ JIA: Early-onset antinuclear antibody–positive juvenile idiopathic and Children’s Health, Institute of Life Course and Medical Sciences,
arthritis; AOSD: Adult-onset Still’s disease; MAS: Macrophage activation University of Liverpool, University Department, Liverpool Women’s Hospital,
syndrome; ANA: Antinuclear antibodies; RF+ JIA: Rheumatoid factor–positive First Floor, Crown Street, Liverpool L8 7SS, UK. 3Department of Clinical
juvenile idiopathic arthritis; Anti-CCP: Anti-cyclic citrullinated peptide; CRP: C- Infection, Microbiology and Immunology, Faculty of Health and Life Sciences,
reactive protein; HLA: Human leukocyte antigen system; VEGF: Vascular Institute of Infection, Veterinary and Ecological Sciences, University of
endothelial growth factor; EC: Endothelial cell; sVEGF-R: Soluble vascular Liverpool, The Ronald Ross Building, 8 West Derby Street, Liverpool L69 7BE,
endothelial growth factor receptor; OPN: Osteopontin; Ang-1: Angiopoietin-1; UK. 4Department of Paediatric Rheumatology, Alder Hey Children’s NHS
TNF: Tumour necrosis factor; IL: Interleukin; MMPs: Matrix metalloproteinases; Foundation Trust, East Prescott Road, Liverpool L14 5AB, UK.
RANK: Receptor activator of nuclear factor-kappaB; MIF: Macrophage
migration inhibitory factor; PTPN22: Protein tyrosine phosphatase non- Received: 2 June 2021 Accepted: 25 July 2021
receptor type-22; STAT4: Signal transducer and activator of transcription-4;
SLC11A1: Solute carrier family-11 member-1; NRAMP1: Natural resistance-
associated macrophage protein-1; WISP3: WNT1-inducible signalling pathway References
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mutated citrullinated vimentin; Anti-CCP: Anti-cyclic citrullinated peptide; 2. Macaubas C, Nguyen K, Milojevic D, Park JL, Mellins ED. Oligoarticular and
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ESR: Erythrocyte sedimentation rate; CRP: C-reactive protein; NSAIDs: Non- 5. Stoll ML, Punaro M. Psoriatic juvenile idiopathic arthritis: a tale of two
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Acknowledgements 7. Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, et al. 2016
This review article was undertaken as part of research funded by a Bolashak Classification criteria for macrophage activation syndrome complicating
Scholarship Award, Kazakhstan Government, to Dr Lina Zaripova to systemic juvenile idiopathic arthritis: a European league against
undertake a PhD at the University of Liverpool, Liverpool, UK, and also by the rheumatism/American College of Rheumatology/Paediatric rheumatology
Wellcome Trust Institutional Strategic Support Fund awarded to the international trials organisation collaborative initiative. Arthritis &
University of Liverpool (grant number 097826/z/11/z). Work was supported rheumatology (Hoboken, NJ). 2016;68(3):566-76.
by the NIHR Alder Hey Clinical Research Facility. The views expressed are 8. Minoia F, Davi S, Horne A, Demirkaya E, Bovis F, Li C, et al. Clinical features,
those of the authors and not necessarily those of the NHS, the NIHR or the treatment, and outcome of macrophage activation syndrome complicating
Department of Health and Social Care. systemic juvenile idiopathic arthritis: a multinational, multicenter study of
362 patients. Arthritis & rheumatology (Hoboken, NJ). 2014;66(11):3160–9.
Authors’ contributions 9. Eng SW, Duong TT, Rosenberg AM, Morris Q, Yeung RS. The biologic basis
LNZ, AM, SEC, MWB, EMB, RAO were involved in the design of the scope of of clinical heterogeneity in juvenile idiopathic arthritis. Arthritis &
the review. LNZ performed literature searches and analysis of content for rheumatology (Hoboken, NJ). 2014;66(12):3463–75.You can also read
